Thymidylate synthetase (TSase) will be isolated from several solid human tumors that are representative of malignancies which are commonly the target of 5-fluorouracil (FU) chemotherapy, and from non-malignant human tissues. The interaction of 5-fluoro-2'-deoxyuridylate (FdUMP) with these enzymes will be studied in detail. We hope to establish whether enzymatic differences are responsible for variability in tumor response to FU. Methods will be investigated and new drugs developed for stabilizing FdUMP binding to human thymidylate synthetase as a means of increasing the clinical chemotherapeutic effectiveness of FU.